Center for International Blood and

Marrow Transplant Research –

Trends in Use of Haploidentical

Transplantation

Number of First Allogeneic HCTs in the

US By Year

CIBMTR, unpublished data 2

0

1000

2000

3000

4000

5000

6000

7000

8000

2010 2011 2012 2013

Numbers of Allogeneic HCTs in the US

By Year and Donor Type

Excludes twins, related CB, 0-1 mism relatives 3

0

500

1000

1500

2000

2500

3000

2010 2011 2012 2013

HLA-id sibling Matched unrelated Something else

Numbers of Allogeneic HCTs in the US

By Year and Donor Type

Excludes twins, related CB, 0-1 mism relatives 4

0

500

1000

1500

2000

2500

3000

2010 2011 2012 2013

HLA id sib

Matched unrelated

Mism unrelated

Haploidentical

Single Cord

Double Cord

Distribution of Graft Sources

5

37%

37%

11%

4%

5% 6%

2010

33%

41%

11%

6% 3%

6%

2013

HLA-id sib

Matched unrelated

Mism unrelated

Haploident

Single Cord

Double Cord

“Alternative Donor” Transplants in the US

by Year and Graft Type

6

0

100

200

300

400

500

600

700

800

900

2010 2011 2012 2013

Mism unrelated

Haploident

Single Cord

Double Cord

Distribution of Alternative Graft Sources

7

41%

14%

20%

25%

2010 N=1646

43%

22%

13%

22%

2013 N=1825

Mism unrelated

Haploident

Single Cord

Double Cord

Umbilical Cord Blood & Haploidentical

Transplants in the US by Year & HLA Match

8

0

50

100

150

200

250

300

350

400

450

2010 2011 2012 2013

Single 5-6/6

Single ≤ 4/6

Double 5-6/6

Double ≤ 4/6

Haploidentical

Numbers of Allogeneic HCTs in US

Caucasians By Year and Donor type

9

0

500

1000

1500

2000

2500

3000

2010 2011 2012 2013

HLA-id sib

Matched unrelated

Mism unrelated

Haploidentical

Single Cord

Double Cord

Total Cord

Numbers of Alternative Donor HCTs in US

Caucasians By Year and Donor type

10

0

100

200

300

400

500

600

700

2010 2011 2012 2013

Mism unrelated

Haploidentical

Single Cord

Double Cord

Total Cord

Numbers of Allogeneic HCTs in African-

Americans By Year and Donor type

11

0

50

100

150

200

250

2010 2011 2012 2013

HLA-id sib

Matched unrelated

Mism unrelated

Haploidentical

Single Cord

Double Cord

Total Cord

Numbers of Alternative Donor HCTs in

African-Americans By Year & Donor type

12

0

20

40

60

80

100

120

2010 2011 2012 2013

Mism unrelated

Haploidentical

Single Cord

Double Cord

Total Cord

Distribution of Graft Sources – 2013

13

32%

46%

10%

4% 3% 5%

Caucasians N=5866

32%

12%

19%

18%

9%

10%

African Americans N=596

HLA-id sib

Matched unrelated

Mism unrelated

Haploident

Single Cord

Double Cord

Numbers of Allogeneic HCTs by Age, Year

and Donor type

14

0

500

1000

1500

2000

2500

3000

2010 2011 2012 2013

<16 Sib <16 Matched unrelated <16 Mism unrelated <16 Haplo <16 Cord 16+ Sib 16+ Matched unrelated 16+ Mism unrelated 16+ Haplo 16+ Cord

Numbers of Allogeneic HCTs in Children

by Year and Donor type

15

0

200

400

600

800

1000

1200

2010 2011 2012 2013

<16 Total

<16 Sib

<16 Matched unrelated

<16 Mism unrelated

<16 Haplo

<16 Cord

Numbers of Allogeneic HCTs in Children

by Year and Donor type

16

0

50

100

150

200

250

300

350

2010 2011 2012 2013

<16 Sib

<16 Matched unrelated

<16 Mism unrelated

<16 Haplo

<16 Cord

Numbers of Allogeneic HCTs in Adults by

Year and Donor type

17

0

500

1000

1500

2000

2500

3000

2010 2011 2012 2013

16+ Sib

16+ Matched unrelated

16+ Mism unrelated

16+ Haplo

16+ Cord

Mother Father

A

9

10

B 11 12

C 13 14

DR 15 16

A

B

C

DR

2 1

3 4

5 6

7 8

Sibling 1 Sibling 2 Sibling 3 Sibling 4

1

3

5

7

9

11

13

15

1

3

5

7

10

12

14

16 16

2

4

6

9 A

B

C

DR

A

B

C

DR 8

11

13

15

A

B

C

DR

2

4

6

8

14

12

10

DR

C

B

A

9

Patient

1

3

5

7

11

13

15

A

B

C

DR

HLA Inheritance

Mother Father

A

31

10

B 11 12

C 13 14

DR 15 16

A

B

C

DR

2 1

3 4

5 6

7 8

Child 1 Sibling 2 Sibling 3 Child 2

1

3

5

7

9

32

33

34

1

3

5

7

10

12

14

16 24

2

4

6

9 A

B

C

DR

A

B

C

DR 8

11

13

15

A

B

C

DR

2

4

6

8

23

22

21

DR

C

B

A

9

Patient

1

3

5

7

11

13

15

A

B

C

DR

HLA Inheritance

HLA-haploidentical BMT circa 1990

C Anasetti et al., Hum Immunol 29:79, 1990

Ablative conditioning

T cell-replete bone marrow

CsA + MTX prophylaxis

Probability of event-free survival in 66 patients who received transplantation in remission and 38 patients

who received transplantation in relapse.

Aversa F et al. JCO 2005;23:3447-3454 ©2005 by American Society of Clinical Oncology

Cumulative incidence of leukemia relapse at 2 years for

patients with acute lymphoblastic leukemia (ALL; A) or

acute myeloid leukemia (AML; B) who were in either

hematologic remission (CR; solid lines) or relapse (REL;

dotted lines) at transplantation.

Aversa F et al. JCO 2005;23:3447-3454

©2005 by American Society of Clinical Oncology

Cumulative incidence of transplant-related deaths at 2 years for patients with acute lymphoblastic leukemia (ALL; A) or acute myeloid leukemia (AML; B) who were in either

hematologic remission (solid lines) or relapse (dotted lines) at transplantation.

Aversa F et al. JCO 2005;23:3447-3454

©2005 by American Society of Clinical Oncology

Cyclophosphamide-induced tolerance

Proliferating

ALLOREACTIVE

cells are killed

Non-proliferating

non-alloreactive

cells are spared

anti-CMV

anti-HSV

anti-CMV

anti-HSV

PT/Cy decreases GVHD after haploidentical HCT

Acute GVHD II-IV Acute GVHD III-IV

Chronic GVHD Severe chronic GVHD

MUD

MSD

Haplo

Haplo

MUD MSD/

Haplo

MUD MSD/

A Bashey et al. J Clin Oncol 31:1310, 2013

Only recipients of haplo grafts got PT/Cy

Haploidentical versus double cord HCT

after reduced intensity conditioning

BMT CTN 0603 (haplo) and BMT CTN 0604

(double cord)

Parallel phase II trials (n=50/trial) of alternative

donor stem cell transplantation after

fludarabine/200 cGy TBI-based conditioning

Acute leukemia in CR, lymphoma

Hypothesis: Survival at six months is >60%

(CIBMTR benchmark for unrelated HCT)

Trials conducted at 16 or 17 centers each,

completed within 18 months

Patient Characteristics

CTN 0604

dUCB (N=50)

CTN 0603

HaploBM (N=50)

Median age

(range)

58

(16-69)

48

(17-70)

Primary disease

ALL

AML

Other leukemia

Lymphoma

12%

58%

2%

28%

12%

44%

6%

38%

Treatment Regimens

0603

0604

Graft-versus-host disease

28% 26%

0604 (cord) 0603 (haplo)

Cu

mu

lati

ve i

ncid

en

ce

(%

)

Ch

ron

ic G

VH

D

Months after transplantation Months after transplantation

Ac

ute

GV

HD

Cord (0604) Haplo (0603)

BMT CTN 0603/0604 Non-relapse mortality and relapse

Cu

mu

lati

ve I

ncid

en

ce,

% 100

0

20

40

60

80

Months Post Transplant 0 8 16 32 24 4 12 36 28 20 40

8%

cord

haplo

28%

Months Post Transplant 0 8 16 32 24 4 12 36 28 20 40

cord

haplo 50% 52% 58%

36% 34% 32%

Non-relapse mortality Relapse

BMT CTN 0603/0604: Survival

Months Post Transplant

Pro

bab

ilit

y,

%

100

0

20

40

60

80

0 24 12 36

68%

54% 54%

52% 46%

39%

84%

74% haplo

cord

100

0

20

40

60

80

Months Post Transplant 0 24 12 36

haplo: 35%

cord: 36%

cord: 38%

haplo: 40%

Overall survival Progression-free survival

The results of BMT CTN 0603 and 0604

establish which of the following?

A. Non-relapse mortality is higher after cord

blood than after haplo HCT

B. Relapse is higher after haplo than after

cord blood HCT

C. Progression-free survival after cord

blood or haploHCT is not significantly

different

D. All of the above

E. None of the above

Answer: “E” (none of the above). Results from

parallel phase II trials cannot be compared statistically

The results of BMT CTN 0603 and 0604

provide equipoise for a randomized phase III

clinical trial with progression-free survival as

the primary endpoint

BMT CTN 1101 Hypothesis: Two year PFS is similar

after related haplo-BM donor transplantation

or after dUCB transplantation.

BMT CTN 1101: Study Endpoints

Primary • Progression-free survival at 2 yrs Secondary • Engraftment • GVHD • Relapse • TRM • Quality of Life • Cost Effectiveness • Immune reconstitution (planned)

Sample size: n=410 patients over 4 years (approximately 8/month)

BMT CTN 1101 Schema

Patient > 18 and <70 yrs.

Acute leukemia or lymphoma

Available both1) 4-6/6 HLA-matched

UCB units

2) 4-6/8 HLA matched

related donor

Adequate organ function

Performance score >70

Double UCB Haplo-BM

Randomization

Stratified by Transplant Center

BMT CTN 1101

Ancillary and co-accruing studies

Cost-effectiveness analysis (R01-HL116291, PI:

Scott Ramsey)

Easy to read informed consent (ETRIC; BMT CTN

1205)

PBMCs collected (pre-BMT, d28, d56, d180, d365)

and stored for analysis of immune reconstitution

BMT CTN 1101

Eligibility

• Age 18-70

• Diagnoses:

– Acute leukemia, not good risk, in CR

– Relapsed, chemosensitive Hodgkin, large cell, or

mantle cell lymphoma (not eligible for autoSCT)

– Follicular or marginal zone lymphoma, relapsed

after at least two prior regimens

• No matched sibs and BOTH GRAFT SOURCES

AVAILABLE

BMT CTN 1101: Accrual (as of 9/14/14)

Trial opened June 19, 2012

35 centers activated

5 centers pending activation

German cooperative group DKMS joining in

early 2015

114 patients accrued; total target is 410

1101 Will Not Answer All Questions

• Restricted to reduced intensity conditioning in

adults

• Diverse diseases with little power to discern

disease-specific efficacy differences

• Comparison only to double cord transplants

40

GS14-01 Comparison of Haplo and HLA-

Matched Unrelated Donor HCT in AML

• 1982 MUDs; 192 haplos

• AML, all stages

• Age 21-70 years

• 2008-2012, US and a single Italian center

• Post-tx Cy for GVHD prophylaxis in haplos

• Variety of GVHD prophylaxis regimens in unrelated donor HCTs

• Primary outcome: 2 year survival (all surviving patients censored at 2 years)

41

Patient Characteristics - Myeloablative Haplo (N=104) Unrelated (N=1245)

Centers 7 101

Median age 47 y 47 y NS

Sorror Index

0

1

2

3

Unknown

33%

24%

11%

4%

29%

32%

23%

23%

22%

<1%

<.001

Disease status

CR1

CR2+

Not in CR

46%

20%

34%

55%

20%

25%

NS

Year of HCT

2009

2010

2011

2012

11%

13%

35%

41%

23%

24%

29%

25%

<.001

42

Patient Characteristics – Reduced Intensity Haplo (N=104) Unrelated (N=1245)

Centers 17 82

Median age 55 y 62 y <.001

Sorror Index

0

1

2

3

27%

25%

17%

31%

30%

23%

21%

27%

<NS

Disease status

CR1

CR2+

Not in CR

49%

35%

16%

61%

17%

22%

NS

Year of HCT

2008

2009

2010

2011

2012

13%

20%

22%

20%

25%

16%

18%

21%

23%

22%

NS

43

Years 0 1 2

0

100

20

40

60

80

Survival

Ad

juste

d C

um

ula

tive

In

cid

en

ce

, %

A

dju

ste

d P

robabili

ty, %

Years

100

0

20

40

60

80

0 2 1

Treatment-related Mortality

Years 0 2 1

0

100

20

40

60

80

Relapse

Years

100

0

20

40

60

80

0 1 2

Disease-free Survival

Reduced–intensity Conditioning

PT-CY (n=88)

MUD (n=737)

PT-CY (n=88)

MUD (n=737)

PT-CY (n=88)

MUD (n=737)

PT-CY (n=88)

MUD (n=737)

Years 0 1 2

0

100

20

40

60

80

Survival

Ad

juste

d C

um

ula

tive

In

cid

en

ce

, %

A

dju

ste

d P

robabili

ty, %

Years

100

0

20

40

60

80

0 2 1

Treatment-related Mortality

Years 0 2 1

0

100

20

40

60

80

Relapse

Years

100

0

20

40

60

80

0 1 2

Disease-free Survival

Myeloablative Conditioning

PT-CY (n=104)

MUD (n=1245)

PT-CY (n=104)

MUD (n=1245)

PT-CY (n=104)

MUD (n=1245)

PT-CY (n=104)

MUD (n=1245)

What Do We Know?

46

• Haploidentical HCT can be performed with

low GVHD and low early TRM and

acceptable 2-3 year overall mortality

• Haploidentical HCT is increasingly used,

predominantly for patients who do not have

an HLA-matched adult donor

What Don’t We Know?

47

• The long-term outcome of haploidentical HCT,

particularly long-term disease control

• Differences in efficacy by specific blood cancer

• Outcomes in children or non-malignant disease

• Optimal graft type (PB or BM) or preparative

regimen

• Relative efficacy compared to other donor

sources (all studies to date underpowered to

detect 10-15% differences in outcome)

Conclusions

48

• Haploidentical HCT is a valid option in

patients without an HLA-identical adult

donors but there are insufficient data to

recommend it over umbilical cord blood or

HLA-mismatched unrelated donor HCTs

• Given the level of uncertainty regarding the

optimal “alternative donor”, participation in

clinical trials in should be encouraged

What’s Missing? Other Types of Donors

49

0

20

40

60

80

100

120

140

160

180

2010 2011 2012 2013

Twin

0-1 Mism Rel

Related Cord